ArticleMolecular therapy : the journal of the American Society of Gene Therapy2015
Chimeric antigen receptors with mutated IgG4 Fc spacer avoid fc receptor binding and improve T cell persistence and antitumor efficacy.
Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 144 papers.
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Who cites it
144 citing papers in PubMed, 200 citations in OpenAlex.
- Meditope-Enabled Chimeric Antigen Receptors Facilitate Plug-and-Play Control of T Cells.Cancer immunology research · 2026Article
- Potent anti-tumor preclinical efficacy of B7-H3 CAR-T cells in H3G34-mutant, Diffuse Hemispheric Glioma.Neuro-oncology · 2026Article
- Humanized and Charge-Optimized CSPG4-Specific CAR-T Cells show Enhanced Efficacy against Head and Neck Squamous Cell Carcinoma.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- NOT-gated chimeric antigen receptor circuits in T and NK cells.Cell systems · 2026Article
- CAR-T cell therapy in breast cancer management: expanding horizon and overcoming challenges beyond hematologic cancers.Molecular biology reports · 2026Review
- Affinity-matured CD72-targeting nanobody CAR T cells enhance elimination of antigen-low B-cell malignancies.Journal for immunotherapy of cancer · 2025Article
- Article
- CD28 signaling complexes are correlated with patient outcomes in anti-CD19 41BB-costimulation CAR T cell therapy.Journal for immunotherapy of cancer · 2025Article
- Fine tuning towards the next generation of engineered T cells.Nature biomedical engineering · 2025Review
- Enhancement of lentiviral vectors gene delivery against VEGFR2 expressing cells by co-display of the binding and fusogenic moieties: a two molecules targeting approach.Virology journal · 2025Article
- Modulating the PPARγ pathway upregulates NECTIN4 and enhances chimeric antigen receptor (CAR) T cell therapy in bladder cancer.Nature communications · 2025Article
- Cell therapies against brain tumors: Clinical development and emerging prospects.Bioengineering & translational medicine · 2025Review
- Chlorotoxin-directed CAR T cell therapy for recurrent glioblastoma: Interim clinical experience demonstrating feasibility and safety.Cell reports. Medicine · 2025Article
- Engineering resilient CAR T cells for immunosuppressive environment.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Review
- Pooled screening for CAR function identifies novel IL-13Rα2-targeted CARs for treatment of glioblastoma.Journal for immunotherapy of cancer · 2025Article
- Non-signaling but all important: how the linker, hinge, and transmembrane domains in the CAR hold it all together.Frontiers in immunology · 2025Review
- The tumor immune microenvironment: implications for cancer immunotherapy, treatment strategies, and monitoring approaches.Frontiers in immunology · 2025Review
- Tracing the development of CAR-T cell design: from concept to next-generation platforms.Frontiers in immunology · 2025Review
- Antigen-independent activation is critical for the durable antitumor effect of GUCY2C-targeted CAR-T cells.Journal for immunotherapy of cancer · 2024Article
- A platform to deliver single and bi-specific Cas9/guide RNA to perturb genes in vitro and in vivo.Molecular therapy : the journal of the American Society of Gene Therapy · 2024Article
84 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
13 authors at 1 institution in 1 country.
Funding
Abstract
The success of adoptive therapy using chimeric antigen receptor (CAR)-expressing T cells partly depends on optimal CAR design. CARs frequently incorporate a spacer/linker region based on the constant region of either IgG1 or IgG4 to connect extracellular ligand-binding with intracellular signaling domains. Here, we evaluated the potential for the IgG4-Fc linker to result in off-target interactions with Fc gamma receptors (FcγRs). As proof-of-principle, we focused on a CD19-specific scFv-IgG4-CD28-zeta CAR and found that, in contrast to CAR-negative cells, CAR+ T cells bound soluble FcγRs in vitro and did not engraft in NSG mice. We hypothesized that mutations to avoid FcγR binding would improve CAR+ T cell engraftment and antitumor efficacy. Thus, we generated CD19-specific CARs with IgG4-Fc spacers that had either been mutated at two sites (L235E; N297Q) within the CH2 region (CD19R(EQ)) or incorporated a CH2 deletion (CD19Rch2Δ). These mutations reduced binding to soluble FcγRs without altering the ability of the CAR to mediate antigen-specific lysis. Importantly, CD19R(EQ) and CD19Rch2Δ T cells exhibited improved persistence and more potent CD19-specific antilymphoma efficacy in NSG mice. Together, these studies suggest that optimal CAR function may require the elimination of cellular FcγR interactions to improve T cell persistence and antitumor responses.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.